Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia

BELNEU Consortium; EU EOD Consortium; Stéphanie Philtjens; Sara Van Mossevelde; Julie van der Zee; Eline Wauters; Lubina Dillen; Mathieu Vandenbulcke; Rik Vandenberghe; Adrian Ivanoiu; Anne Sieben; Christiana Willems; Luisa Benussi; Roberta Ghidoni; Giuliano Binetti; Barbara Borroni; Alessandro Padovani; Pau Pastor; Monica Diez-Fairen; Miquel Aguilar; Alexandre de Mendonça; Gabriel Miltenberger-Miltényi; Isabel Hernández; Merce Boada; Agustín Ruiz; Benedetta Nacmias; Sandro Sorbi; Maria Rosário Almeida; Isabel Santana; Jordi Clarimón; Alberto Lleó; Giovanni B. Frisoni; Raquel Sanchez-Valle; Albert Lladó; Estrella Gómez-Tortosa; Ellen Gelpi; Marleen Van den Broeck; Karin Peeters; Patrick Cras; Peter P. De Deyn; Sebastiaan Engelborghs; Marc Cruts; Christine Van Broeckhoven; on behalf of the  BELNEU Consortium; and the  EU EOD Consortium

doi:10.1016/j.neurobiolaging.2018.02.011

Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia

BELNEU Consortium, EU EOD Consortium, Stéphanie Philtjens, Sara Van Mossevelde, Julie van der Zee, Eline Wauters, Lubina Dillen, Mathieu Vandenbulcke, Rik Vandenberghe, Adrian Ivanoiu, Anne Sieben, Christiana Willems, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Barbara Borroni, Alessandro Padovani, Pau Pastor, Monica Diez-Fairen, Miquel AguilarAlexandre de Mendonça, Gabriel Miltenberger-Miltényi, Isabel Hernández, Merce Boada, Agustín Ruiz, Benedetta Nacmias, Sandro Sorbi, Maria Rosário Almeida, Isabel Santana, Jordi Clarimón, Alberto Lleó, Giovanni B. Frisoni, Raquel Sanchez-Valle, Albert Lladó, Estrella Gómez-Tortosa, Ellen Gelpi, Marleen Van den Broeck, Karin Peeters, Patrick Cras, Peter P. De Deyn, Sebastiaan Engelborghs, Marc Cruts, Christine Van Broeckhoven, on behalf of the BELNEU Consortium , and the EU EOD Consortium

Research output: Contribution to journal › Article › peer-review

Abstract

We investigated the genetic role of sortilin (SORT1) in frontotemporal dementia (FTD). SORT1 is the neuronal receptor for granulin, encoded by the progranulin gene (GRN), a major causal gene for inherited FTD. In Belgian cohorts of 636 FTD patients and 1066 unaffected control individuals, we identified 5 patient-only nonsynonymous rare variants in SORT1. Rare variant burden analysis showed a significant increase in rare coding variants in patients compared to control individuals (p = 0.04), particularly in the β-propeller domain (p = 0.04), with 2 rare variants located in the predicted binding site for GRN (p = 0.001). We extended these observations by analyzing 3 independent patient/control cohorts sampled in Spain, Italy, and Portugal by partners of the European Early-Onset Dementia Consortium, together with 1155 FTD patients and 1161 control persons. An additional 7 patient-only nonsynonymous variants were observed in SORT1 in European patients. Meta-analysis of the rare nonsynonymous variants in the Belgian and European patient/control cohorts revealed a significant enrichment in FTD patients (p = 0.006), establishing SORT1 as a genetic risk factor for FTD.

Original language	English
Journal	Neurobiology of Aging
DOIs	https://doi.org/10.1016/j.neurobiolaging.2018.02.011
Publication status	Accepted/In press - Jan 1 2018

Keywords

Frontotemporal dementia
Genetic association
Granulin
Rare variants
Sortilin

ASJC Scopus subject areas

Neuroscience(all)
Ageing
Clinical Neurology
Developmental Biology
Geriatrics and Gerontology

Access to Document

10.1016/j.neurobiolaging.2018.02.011

Cite this

BELNEU Consortium, EU EOD Consortium, Philtjens, S., Van Mossevelde, S., van der Zee, J., Wauters, E., Dillen, L., Vandenbulcke, M., Vandenberghe, R., Ivanoiu, A., Sieben, A., Willems, C., Benussi, L., Ghidoni, R., Binetti, G., Borroni, B., Padovani, A., Pastor, P., Diez-Fairen, M., ... EU EOD Consortium, A. T. (Accepted/In press). Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia. Neurobiology of Aging. https://doi.org/10.1016/j.neurobiolaging.2018.02.011

BELNEU Consortium, EU EOD Consortium, Philtjens, S, Van Mossevelde, S, van der Zee, J, Wauters, E, Dillen, L, Vandenbulcke, M, Vandenberghe, R, Ivanoiu, A, Sieben, A, Willems, C, Benussi, L , Ghidoni, R , Binetti, G , Borroni, B, Padovani, A, Pastor, P, Diez-Fairen, M, Aguilar, M, de Mendonça, A, Miltenberger-Miltényi, G, Hernández, I, Boada, M, Ruiz, A, Nacmias, B, Sorbi, S, Almeida, MR, Santana, I, Clarimón, J, Lleó, A, Frisoni, GB, Sanchez-Valle, R, Lladó, A, Gómez-Tortosa, E, Gelpi, E, Van den Broeck, M, Peeters, K, Cras, P, De Deyn, PP, Engelborghs, S, Cruts, M, Van Broeckhoven, C, BELNEU Consortium , OBOT & EU EOD Consortium, AT 2018, 'Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia', Neurobiology of Aging. https://doi.org/10.1016/j.neurobiolaging.2018.02.011

@article{a15cd169943146479c51a648917049c0,

title = "Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia",

abstract = "We investigated the genetic role of sortilin (SORT1) in frontotemporal dementia (FTD). SORT1 is the neuronal receptor for granulin, encoded by the progranulin gene (GRN), a major causal gene for inherited FTD. In Belgian cohorts of 636 FTD patients and 1066 unaffected control individuals, we identified 5 patient-only nonsynonymous rare variants in SORT1. Rare variant burden analysis showed a significant increase in rare coding variants in patients compared to control individuals (p = 0.04), particularly in the β-propeller domain (p = 0.04), with 2 rare variants located in the predicted binding site for GRN (p = 0.001). We extended these observations by analyzing 3 independent patient/control cohorts sampled in Spain, Italy, and Portugal by partners of the European Early-Onset Dementia Consortium, together with 1155 FTD patients and 1161 control persons. An additional 7 patient-only nonsynonymous variants were observed in SORT1 in European patients. Meta-analysis of the rare nonsynonymous variants in the Belgian and European patient/control cohorts revealed a significant enrichment in FTD patients (p = 0.006), establishing SORT1 as a genetic risk factor for FTD.",

keywords = "Frontotemporal dementia, Genetic association, Granulin, Rare variants, Sortilin",

author = "{BELNEU Consortium} and {EU EOD Consortium} and St{\'e}phanie Philtjens and {Van Mossevelde}, Sara and {van der Zee}, Julie and Eline Wauters and Lubina Dillen and Mathieu Vandenbulcke and Rik Vandenberghe and Adrian Ivanoiu and Anne Sieben and Christiana Willems and Luisa Benussi and Roberta Ghidoni and Giuliano Binetti and Barbara Borroni and Alessandro Padovani and Pau Pastor and Monica Diez-Fairen and Miquel Aguilar and {de Mendon{\c c}a}, Alexandre and Gabriel Miltenberger-Milt{\'e}nyi and Isabel Hern{\'a}ndez and Merce Boada and Agust{\'i}n Ruiz and Benedetta Nacmias and Sandro Sorbi and Almeida, {Maria Ros{\'a}rio} and Isabel Santana and Jordi Clarim{\'o}n and Alberto Lle{\'o} and Frisoni, {Giovanni B.} and Raquel Sanchez-Valle and Albert Llad{\'o} and Estrella G{\'o}mez-Tortosa and Ellen Gelpi and {Van den Broeck}, Marleen and Karin Peeters and Patrick Cras and {De Deyn}, {Peter P.} and Sebastiaan Engelborghs and Marc Cruts and {Van Broeckhoven}, Christine and {BELNEU Consortium}, {on behalf of the} and {EU EOD Consortium}, {and the}",

year = "2018",

month = jan,

day = "1",

doi = "10.1016/j.neurobiolaging.2018.02.011",

language = "English",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia

AU - BELNEU Consortium

AU - EU EOD Consortium

AU - Philtjens, Stéphanie

AU - Van Mossevelde, Sara

AU - van der Zee, Julie

AU - Wauters, Eline

AU - Dillen, Lubina

AU - Vandenbulcke, Mathieu

AU - Vandenberghe, Rik

AU - Ivanoiu, Adrian

AU - Sieben, Anne

AU - Willems, Christiana

AU - Benussi, Luisa

AU - Ghidoni, Roberta

AU - Binetti, Giuliano

AU - Borroni, Barbara

AU - Padovani, Alessandro

AU - Pastor, Pau

AU - Diez-Fairen, Monica

AU - Aguilar, Miquel

AU - de Mendonça, Alexandre

AU - Miltenberger-Miltényi, Gabriel

AU - Hernández, Isabel

AU - Boada, Merce

AU - Ruiz, Agustín

AU - Nacmias, Benedetta

AU - Sorbi, Sandro

AU - Almeida, Maria Rosário

AU - Santana, Isabel

AU - Clarimón, Jordi

AU - Lleó, Alberto

AU - Frisoni, Giovanni B.

AU - Sanchez-Valle, Raquel

AU - Lladó, Albert

AU - Gómez-Tortosa, Estrella

AU - Gelpi, Ellen

AU - Van den Broeck, Marleen

AU - Peeters, Karin

AU - Cras, Patrick

AU - De Deyn, Peter P.

AU - Engelborghs, Sebastiaan

AU - Cruts, Marc

AU - Van Broeckhoven, Christine

AU - BELNEU Consortium , on behalf of the

AU - EU EOD Consortium, and the

PY - 2018/1/1

Y1 - 2018/1/1

N2 - We investigated the genetic role of sortilin (SORT1) in frontotemporal dementia (FTD). SORT1 is the neuronal receptor for granulin, encoded by the progranulin gene (GRN), a major causal gene for inherited FTD. In Belgian cohorts of 636 FTD patients and 1066 unaffected control individuals, we identified 5 patient-only nonsynonymous rare variants in SORT1. Rare variant burden analysis showed a significant increase in rare coding variants in patients compared to control individuals (p = 0.04), particularly in the β-propeller domain (p = 0.04), with 2 rare variants located in the predicted binding site for GRN (p = 0.001). We extended these observations by analyzing 3 independent patient/control cohorts sampled in Spain, Italy, and Portugal by partners of the European Early-Onset Dementia Consortium, together with 1155 FTD patients and 1161 control persons. An additional 7 patient-only nonsynonymous variants were observed in SORT1 in European patients. Meta-analysis of the rare nonsynonymous variants in the Belgian and European patient/control cohorts revealed a significant enrichment in FTD patients (p = 0.006), establishing SORT1 as a genetic risk factor for FTD.

AB - We investigated the genetic role of sortilin (SORT1) in frontotemporal dementia (FTD). SORT1 is the neuronal receptor for granulin, encoded by the progranulin gene (GRN), a major causal gene for inherited FTD. In Belgian cohorts of 636 FTD patients and 1066 unaffected control individuals, we identified 5 patient-only nonsynonymous rare variants in SORT1. Rare variant burden analysis showed a significant increase in rare coding variants in patients compared to control individuals (p = 0.04), particularly in the β-propeller domain (p = 0.04), with 2 rare variants located in the predicted binding site for GRN (p = 0.001). We extended these observations by analyzing 3 independent patient/control cohorts sampled in Spain, Italy, and Portugal by partners of the European Early-Onset Dementia Consortium, together with 1155 FTD patients and 1161 control persons. An additional 7 patient-only nonsynonymous variants were observed in SORT1 in European patients. Meta-analysis of the rare nonsynonymous variants in the Belgian and European patient/control cohorts revealed a significant enrichment in FTD patients (p = 0.006), establishing SORT1 as a genetic risk factor for FTD.

KW - Frontotemporal dementia

KW - Genetic association

KW - Granulin

KW - Rare variants

KW - Sortilin

UR - http://www.scopus.com/inward/record.url?scp=85044008028&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85044008028&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2018.02.011

DO - 10.1016/j.neurobiolaging.2018.02.011

M3 - Article

AN - SCOPUS:85044008028

JO - Neurobiology of Aging

JF - Neurobiology of Aging

SN - 0197-4580

ER -

Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this